The formation of antigen (Ag)-specific memory is key for the success of vaccines and for immunotherapy of infections and cancer, but the cells that carry immunological memory are also implicated in numerous human disease. T and B cells have been considered sole carriers of immunological memory, so efforts to diagnose, treat or prevent immune diseases have been focused on these lymphocytes. However, there is mounting evidence that this T and B cell-centric paradigm requires revision: preliminary work has shown that long-lived memory can also be acquired by a discrete subset of liver-resident natural killer (NK) cells, which arise in lymph nodes (LNs) upon encounter of Ag presenting dendritic cells (DCs). To date, NK memory has been documented for four distinct haptens and six viral Ags. The goals of this project are to elucidate mechanistically this novel NK cell function and to understand its pathophysiological consequences. Two specific aims will be pursued: Aim 1 will investigate the mechanisms and consequences of memory NK cell priming in LNs. To this end, we will characterize the 'naive' memory-capable NK cell subset(s) and investigate the molecular mechanism that provides Ag-specificity; we will analyze the dynamics of NK cell interactions with DCs In LNs; and we will explore whether human NK cells can also acquire memory. Aim 2 will characterize recall responses of primed NK cells using haptens and influenza virus as models. Here, we will investigate memory NK cell trafficking at steady state and upon rechallenge; analyze memory NK cell mediated protection during influenza infection; and explore the role of negative costimulation in memory NK cell generation, persistence and function.